The major current focus of this project is a randomized, multicenter, double-blind, placebo-controlled Phase III study to evaluate the effect of valaciclovir in preventing the transmission of herpes simplex virus (HSV) in heterosexual couples discordant for the presence of herpes simplex type 2 virus (HSV-2) antibody. The seropositive source partner is randomized to receive valaciclovir 500 mg once daily or placebo for 8 months, and the susceptible seronegative partner is monitored for clinical and subclinical (serological) acquisition of HSV. A total of 1500 couples will be randomized into the study, at approximately 100 outpatient centers in the United States, Canada and Europe. At the NIH, 32 couples have been randomized into this study, with an aim of enrolling a total of 40 couples.